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Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.

Purpose - The eye and its accessory structures, the optic nerve and the extraocular muscles, form a complex dynamic system. In vivo magnetic resonance imaging (MRI) of this system in motion can have substantial benefits in understanding oculomotor functioning in health and disease, but has been restricted to date to imaging of static gazes only. The purpose of this work was to develop a technique to image the eye and its accessory visual structures in motion.Methods - Dynamic imaging of the eye was developed on a 3-Tesla MRI scanner, based on a golden angle radial sequence that allows freely selectable frame-rate and temporal-span image reconstructions from the same acquired data set. Retrospective image reconstructions at a chosen frame rate of 57 ms per image yielded high-quality in vivo movies of various eye motion tasks performed in the scanner. Motion analysis was performed for a left-right version task where motion paths, lengths, and strains/globe angle of the medial and lateral extraocular muscles and the optic nerves were estimated.Results - Offline image reconstructions resulted in dynamic images of bilateral visual structures of healthy adults in only ∼15-s imaging time. Qualitative and quantitative analyses of the motion enabled estimation of trajectories, lengths, and strains on the optic nerves and extraocular muscles at very high frame rates of ∼18 frames/s.Conclusions - This work presents an MRI technique that enables high-frame-rate dynamic imaging of the eyes and orbital structures. The presented sequence has the potential to be used in furthering the understanding of oculomotor mechanics in vivo, both in health and disease.

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes, were evaluated by mining GWAS datasets. eQTL analysis identified 1971 and 2078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2 were identified in both tissues. 62.1 % of top cis-eSNPs were within ±50 kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu ) and identified genetically regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes.

The effect of statins on functional status in older patients is unclear. Statins might carry a deleterious effect on muscle function leading to myopathy and therefore affecting functional recovery. We evaluated the relationship between statin exposure at in-hospital rehabilitation admission and functional outcome at discharge. This was a retrospective cohort study of older patients 70 years and older consecutively admitted to an in-hospital rehabilitation after an acute hospitalization. Statin exposure was measured at the time of rehabilitation admission. Functional status was defined with the Barthel Index (BI) score at the time of discharge. A multi-variable linear regression model was used to evaluate the association between statin exposure and functional status at discharge adjusting for potential confounders through a propensity score for statin exposure. A total of 2435 patients were included. The cohort had a mean age of 81.1 years. Of these 9% (n=220) were on statins at the time of admission. In the multi-variable analysis, the use of statins at the time of admission was independently associated with an improved functional status at discharge (point estimate 5.2; 95% confidence interval 1.5-8.9; p<0.01) after adjusting for relevant confounders. Patients who were receiving statins at the time of admission had a BI score 5 points higher compared to those who were not receiving statins. The use of statins was overall safe in a group of co-morbid older patients undergoing rehabilitation training after an acute hospitalization. Additionally, a possible benefit was found given the positive association between statin use and higher functional status at discharge.